17 α-Acyl-4-aza-5a-androst-1-en-3-ones as 5 alpha-reductase inhibitors

ABSTRACT

17β-Acyl-4-aza-5α-androst-1-en-3-ones of the formula: ##STR1## wherein R is selected from hydrogen, methyl and ethyl and 
     R 2  is a monovalent radical selected from straight carbons, or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or 1 or more halo (Cl or Br) substituents, aralkyl selected from benzyl and phenethyl and heterocyclic selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl; 
     and R&#39;, R&#34; and R&#39;&#34; are each selected from hydrogen and methyl and pharmaceutical formulation of the above compounds are active as testosterone 5α-reductase inhibitors and thus are useful topically for treatment of acne, seborrhea, female hirsutism, and systemically in treatment of benign prostatic hypertrophy.

This is a continuation of application Ser. No. 800,624, filed Nov. 21,1985, now abandoned, which in turn is a continuation of application Ser.No. 584,061, filed Feb. 27, 1984, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is concerned with novel17β-acyl-4-aza-5α-androst-1-en-3-one compounds and the use of suchcompounds as testosterone-5α-reductase inhibitors.

DESCRIPTION OF THE PRIOR ART

It is well known in the art that certain undesirable physiologicalmanifestations, such as acne vulgaris, seborrhea, female hirsutism, andmale pattern baldness and benign prostatic hypertrophy, are the resultof hyperandrogenic stimulation caused by an excessive accumulation oftestosterone or similar androgenic hormones in the metabolic system.Early attempts to provide a chemotherapeutic agent to counter theundesirable results of hyperandrogenicity resulted in the discovery ofseveral steroidal antiandrogens having undesirable hormonal activitiesof their own. The estrogens, for example, not only counteract the effectof the androgens but have a feminizing effect as well. Non-steroidalantiandrogens have also been developed, for example,4'-nitro-3'-trifluoromethylisobutyranilide. See Neri et al., Endo., Vol.91, Nol 2 (1972). However, these products, though devoid of hormonaleffects, are peripherally active, competing with the natural androgensfor receptor sites, and hence have a tendency to feminize a male host orthe male fetus of a female host.

It more recently became known in the art that the principal mediator ofandrogenic activity in some target organs is 5α-dihydrotestosterone, andthat it is formed locally in the target organ by the action oftestosterone-5α-reductase. It therefore has been postulated anddemonstrated that inhibitors of testosterone-5α-reductase will serve toprevent or lessen symptoms of hyperandrogenic stimulation. Nayfeh etal., Steroids, 14, 269 (1969) demonstrated in vitro that methyl4-androsten-3-one-17β-carboxylate was a testosterone-5α-reductaseinhibitor. Then Voigt and Hsia, Endocrinology, 92, 1216 (1973), CanadianPat. No. 970,692, demonstrated that the above ester and the parent freeacid, 4-androsten-3-one-17β-carboxylic acid are both active inhibitorsof testosterone-5α-reductase in vitro. They further demonstrated thattopical application of either testosterone or 5α-dihydrotestosteronecaused enlargement of the female hamster flank organ, or androgendependent sebaceous structure. However, concomitant administration of4-androsten-3-one-17β-carboxylic acid or its methyl ester inhibited theresponse elicited by testosterone but did not inhibit the responseelicited by 5α-dihydrotestosterone. These results were interpreted asindicating that the compounds were antiandrogenic by virtue of theirability to inhibit testosterone-5α-reductase.

A number of 4-aza steroid compounds are known. See, for example, U.S.Pat. Nos. 2,227,876; 3,239,417; 3,264,301; and 3,285,918; French Pat.No. 1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62, 4, pp. 638-640(1973); Doorenbos and Brown, J. Pharm. Sci., 60, 8, pp. 1234-1235(1971); and Doorenbos and Kim, J. Pharm. Sci., 63, 4, pp. 620-622(1974).

In addition U.S. Pat. Nos. 4,377,584 and 4,220,775 of Rasmusson et al.describe a group of 4-aza-5α-17β-substituted-5α-androsten-3-ones whichare said to be useful in the treatment of hyperandrogenic conditions.However, none of the cited references suggest that any of the novel17β-acyl-4-aza-5α-androst-1-en-3-ones of the present invention wouldhave utility as highly potent testosterone-5α-reductase inhibitors.

DESCRIPTION OF THE INVENTION

The present invention is concerned with novel17β-acyl-4-aza-5α-androst-1-en-3-one compounds, processes for theirpreparation, pharmaceutical formulations comprising the novel compoundsas active ingredients and methods of inhibitingtestosterone-5α-reductase and of treating hyperandrogenic conditionswith the novel compounds or their pharmaceutical formulations.

The present invention is concerned with17β-acyl-4-aza-5α-androst-1-en-3-one compounds of the formula: ##STR2##wherein R is selected from hydrogen, methyl and ethyl and

R² is a monovalent radical selected from straight and branched chainalkyl of from 1-12 carbons, or monocyclic aryl optionally containing 1or more lower alkyl substituents of from 1-2 carbon atoms and/or 1 ormore halo (Cl or Br) substituents, aralkyl selected from benzyl andphenethyl and heterocyclic selected from 2- or 4-pyridyl, 2-pyrrolyl,2-furyl or thiophenyl and R', R" and R'" are each selected from hydrogenand methyl.

A preferred embodiment of the novel compounds of our invention isrepresented by the formula: ##STR3## wherein R is hydrogen, methyl orethyl, and

R³ is branched chain alkyl, or cycloalkyl of from 4-8 carbons.

Representative compounds of the present invention including thefollowing:

17β-(t-butylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(isobutylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(isooctylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(n-octylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(1,1-diethylbutylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(neopentylcarbamoyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(tert-amylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(tert-hexylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one;

17β-(5-butylcarbonyl)-4-aza-4-methyl-5α-androst-1-en-3-one; and thecorresponding compounds wherein the 4-methyl substituent is replaced ineach of the above named compounds by a hydrogen or an ethyl radical.

Also included as representative compounds are any of the above indicatedcompounds having the alkyl of the alkyl carbonyl substituent replaced bya methyl-, ethyl-, propyl-, i-propyl-, butyl-, phenyl-, 2-, 3- or4-tolyl-, xylyl-, 2-bromo- or 2-chlorophenyl-, 2,6-dichloro- or a2,6-dibromophenyl carbonyl substituent or a heterocyclic substituentselected from 2 or 4-pyridyl, 2-pyrrolyl, 2-furyl or 2-thiophenyl.

The novel compounds of formula I of the present invention are preparedby a method starting with the known steroid ester of the formula:##STR4## which includes the stages of (1) dehydrogenating said startingmaterial to produce the corresponding compound containing a double bondin the 1,2-position of the A-ring, (2) converting the 17-carbomethoxysubstituent into a 17β-acyl substituent and, if desired (3) alkylatingthe A-ring nitrogen to introduce 4-methyl or 4-ethyl substituents intothe A-ring. In carrying out the process of the present invention, it isessential that stage (1) dehydrogenation of the 1,2-position of thesteroid A-ring be carried out using a 4-aza-5α-androsten-3-one compoundhaving no substituent other than hydrogen attached to the A-ringnitrogen. Stage (2) may consist of one or more chemical steps and ifdesired may take place before stage (1) for following stage (1) or stage(3).

In accordance with the process of the present invention, the products ofour invention are formed by (1) heating a17β-alkoxycarbonyl-4-aza-5α-androstan-3-one compound III with adehydrogenating agent such as benzeneselenic anhydride in refluxingchlorobenzene to form a 17β-alkoxycarbonyl-4-aza-5α-androst-1-en-3-one(IV). (2) the formed 5α-androst-1-en-3-one compound from step (1) isreacted with sodium hydride and under anhydrous conditions in a neutralsolvent such as dimethylformamide, (2) contacting the resulting reactionmixture with an alkyl (methyl or ethyl) iodide to form the corresponding17β-alkoxycarbonyl-4-alkyl-4-aza-5α-androst-1-en-3-one (V), (3)subsequently hydrolyzing said17β-alkoxycarbonyl-4-alkyl-4-aza-5α-androst-1-en-3-one with a strongbase such as aqueous methanolic potassium hydroxide at the refluxtemperature, followed by acidification and isolation of the resultingsteroidal acid, 17β-carboxy-4-alkyl-4-aza-5α-androst-1-en-3-one (VI),(4) said steroidal acid is then converted to its corresponding2-thiopyridyl ester by refluxing with triphenyl phosphine and2,2'-dipyridyl disulfide in an inert solvent and the product17β-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5α-androst-1-en-3-one (VII) isisolated by chromatography on silica, (5) said pyridylthio ester is thenreacted with an R² -Li or an R² MgX (X=Cl, Br) compound such assec-butylmagnesium chloride in tetrahydrofuran to form the desiredproduct 17β-(sec-butylcarbonyl)-4-alkyl-4-aza-5α-androst-1-en-3-one(VIII) which is isolated by chromatography on silica gel. When theprevious reaction is carried out using an R² MgX or, an R² -Li compoundin place of sec-butylmagnesium chloride, the corresponding17β-(acyl)-4-alkyl-4-aza-5α-androst-1-en-3-one is prepared wherein acylis R² carbonyl.

In accordance with the process of our invention, the corresponding17β-acyl-4-aza-5α-androst-1-en-3-one XV is readily prepared from the17β(alkoxycarbonyl)-4-aza-5α-androsten-3-one (IV) by repeating the aboveseries of reaction steps but omitting step 2 hereinabove, i.e.,treatment of the 4-aza-5α-androst-1-en-3-one with sodium amide followedby methyl or ethyl iodide.

In accordance with a further alternate process of preparing thecompounds of our invention, having only hydrogen as the sole substituenton the ring A-nitrogen, the Δ' double bond in the A-ring is introducedas the last step of the process. Thus, a17β-alkoxycarbonyl-4-aza-5α-androstan-3-one (III) is hydrolyzed to thecorresponding steroidal acid, 17β-carboxy-4-aza-5α-androstan-3-one, (IX)which, in turn, is converted to the corresponding thiopyridyl ester,17β-(2-pyridylthiocarbonyl)-4-aza-5α-androstan-1-one (X) followed bytreatment of the ester with an R² MgX or R² Li compound wherein R² is asdefined hereinabove to form a 17β-(acyl)-4-aza-5α-androstan-3-one (XI)which is dehydrogenated as previously described to produce compound XIV,17β-(acyl)-4-aza-5α-androst-1-en-3-one.

The 16 methyl derivative wherein R'" is methyl are prepared from known16-methyl-17-acyl-4-methyl-4-aza-5α-androstan-3-ones, e.g.4,16β-dimethyl-17β-acetyl-4-aza-5α-androstan-3-one by knowndehydrogenation procedures for 4-methyl-4-aza compounds to produce thecorresponding 4,16β-dimethyl-17β-acetyl-4-aza-5α-androst-1-en-3-one.

The above reactions are schematically represented in the followingstructural outline: ##STR5## wherein X is a 2-pyridylthio substituentand R² is defined as hereinabove.

The compounds of the present invention, prepared in accordance with themethod described above, are, as already described, potent antiandrogensby virtue of their ability to specifically inhibittestosterone-5α-reductase.

Accordingly, the present invention is particularly concerned withproviding a method of treating the hyperandrogenic conditions of acnevulgaris, seborrhea, and female hirsutism by topical administration, anda method of treating all of the above conditions as well as benignprostatic hypertrophy, by parenteral administration, of the novelcompounds of the present invention.

The present invention is thus also concerned with providing suitabletopical and parenteral pharmaceutical formulations for use in the novelmethods of treatment of the present invention.

The compositions containing the compounds of the present invention asthe active ingredient for use in the treatment of benign prostatichypertrophy can be administered in a wide variety of therapeutic dosageforms in conventional vehicles for systemic administration, as, forexample, by oral administration in the form of tablets, capsules,solutions, or suspensions, of by intravenous injection. The daily dosageof the products may be varied over a wide range varying from 50 to 2,000mg. The compositions are preferably provided in the form of scoredtablets containing 5, 10, 25, 50, 100, 150, 250, and 500 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 1 mg to about 50 mg/kg of bodyweight per day. Preferably the range is from about 1 mg to 7 mg/kg ofbody weight per day. These dosages are well below the toxic dose of theproduct. Capsules containing the product of this invention can beprepared by mixing an active compound of the present invention withlactose and magnesium stearate, calcium stearate, starch, talc, or othercarriers, and placing the mixture in gelatin capsule. Tablets may beprepared by mixing the active ingredient with conventional tabletingingredients such as calcium phosphate, lactose, corn starch or magnesiumstearate. The liquid forms in suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methylcellulose and the like. Other dispersing agents which maybe employed include glycerin and the like. For parenteral administrationsterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservative are employed whenintravenous administration is desired.

For the treatment of acne vulgaris, seborrhea, female hirsutism, thecompounds of the present invention are administrated in the formula ofpharmaceutical composition comprising the active compound in combinationwith a pharmacologically acceptable carrier adapted for topicaladministration. These topical pharmaceutical compositions may be in theform of cream, ointment, gel or aerosol formulation adopted forapplication to the skin. These topical pharmaceutical compositionscontaining the compounds of the present invention ordinarily includeabout 0.1% to 15%, preferably about 5%, of the active compound, inadmixture with about 95% of vehicle.

The method of preparing the novel compounds of the present invention,already described above in general terms, may be further illustrated bythe following examples.

EXAMPLE 1 22-Methyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione ##STR6##

To a solution of 7.2 g ofS-(2-pyridyl)-3-oxo-4-aza-5α-androst-1-ene-17β-thiocarboxylate in 288 mlof tetrahydrofuran was added at -78° C. 33.6 ml of 1.3M S-butylmagnesiumchloride. After 30 minutes at -78° C. the solution came to roomtemperature and was treated with saturated aqueous NaCl solution. Theproduct was extracted into dichloromethane and was washed with saturatedaqueous NaCl solution and 10% aqueous NaOH solution, then dried andconcentrated. The residue was eluted through 430 g of silica gel with9:1 dichloromethane-acetone to give 4.5 g of the product, m.p. 246°-249°C.

When the procedure is repeated using the following reagents, theindicated product is obtained.

    ______________________________________                                        Starting                                                                      Material     Reagent      Product                                             ______________________________________                                        S--(2-pyridyl)3-                                                                           2-pyrrolyl mag-                                                                            17β-(2-pyrrolyl-                               oxo-4-aza-5α-                                                                        nesium chloride                                                                            carbonyl)-4-aza-                                    androst-1-en-             5α-androst-1-en-                              17β-thiocarboxylate  3-one                                                                         m.p. 294-296° C.                             S-(2-pyridyl)3-                                                                            sec-butyl mag-                                                                             4,22-dimethyl-4-                                    oxo-4-methyl-5α-                                                                     nesium chloride                                                                            aza-21-nor-5α-                                androst-1-en-17β-    chol-1-en-3,20-dione                                thiocarboxylate           m.p. 134-136° C.                             S-(2-pyridyl)3-                                                                            2-pyrrolyl mag-                                                                            4-methyl-17β-(2-                               oxo-4-methyl-4-                                                                            nesium chloride                                                                            pyrrolylcarbonyl)-                                  aza-5α-androst-     4-aza-5α-androst-                             1-en-17β-thio-       1-en-3-one                                          carboxylate               m.p. 234-238° C.                             S-(2-pyridyl)3-                                                                            isobutyl mag-                                                                              23-methyl-4-aza-                                    oxo-4-aza-5α-                                                                        nesium chloride                                                                            21-nor-5α-                                    androst-en-17β-      cholane-3,20-                                       thiocarboxylate           dione                                                                         m.p. 220-222° C.                             ______________________________________                                    

EXAMPLE 2 22-Methyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione ##STR7##

A solution of 21 g of 22-methyl-4-aza-21-nor-5α-cholane-3,20-dione(Step 1) and 29.49 g of benzeneseleninic anhydride in 552 ml ofchlorobenzene was refluxed with water separation for 4 hours. Themixture was concentrated and the residue was redissolved indichloromethane. After washing with 10% aqueous sodium hydroxide, then10% hydrochloric acid and saturated aqueous sodium chloride the solutionwas dried and concentrated to 45 g of yellow residue. This waschromatographed on 1.5 kg of silica gel packed in dichloromethane andeluted with ethyl acetate to give 10.6 g of the product, m.p. 248°-251°C.

When the procedure is repeated using23-methyl-4-aza-21-nor-5α-cholane-3,20-dione as starting material theproduct is obtained is 23-methyl-1-aza-21-nor-5α-chol-1-ene-3,20-dione,m.p. 283°-286° C.

What is claimed is:
 1. A compound of the formula: ##STR8## wherein R isselected from hydrogen, methyl and ethyl andR₂ is branched chain alkylof from 3-12 carbons, R', R", R'" are each selected from hydrogen andmethyl.
 2. A compound of claim 1 having the formula ##STR9## wherein Ris hydrogen, methyl or ethyl andR³ is branched chain alkyl of from 4-8carbon atoms.
 3. A compound of claim 1 wherein the compound is22-methyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione.
 4. A compound of claim1 wherein the compound is4,22-dimethyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione.
 5. A compound ofclaim 1 wherein the compound is23-methyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione.
 6. A method of treatingthe hyperandrogenic condition of acne vulgaris, seborrhea, femalehirsutism, and benign prostatic hypertrophy comprising parenteraladministration to a patient in need of such treatment of atherapeutically effective amount of a compound of formula: ##STR10##wherein R and R² are defined as in claim
 1. 7. The method of claim 6where there is employed a compound of the formula: ##STR11## wherein Ris hydrogen, methyl or ethyl andR² is branched chain alkyl of from 4-8carbon atoms.
 8. A method of inhibiting testosterone 5α-reductase in apatient in need of such inhibiting treatment, comprising administrationto such a patient of a therapeutically effective amount of a compound ofthe formula: ##STR12## wherein R and R² are defined as in claim 1,R' ishydrogen or methyl, R" is hydrogen or β-methyl, R"' is hydrogen,α-methyl or β-methyl.
 9. The compound of claim 8 wherein there isemployed a compound of the formula: ##STR13## wherein R is selected fromhydrogen, methyl and ethyl andR³ is branched chain alkyl of from 4-8carbon atoms.
 10. A pharmaceutical composition comprising apharmaceutically acceptable carrier and an effective amount of acompound of formula: ##STR14## wherein R and R² are defined as inclaim
 1. 11. The composition of claim 10 wherein there is employed acompound of the formula: ##STR15## wherein R is hydrogen, methyl orethyl, andR³ is branched chain alkyl of from 4-8 carbon atoms.